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PLoS One. 2014 Apr 23;9(4):e96283. doi: 10.1371/journal.pone.0096283. eCollection 2014.

Opposing effects of PI3K/Akt and Smad-dependent signaling pathways in NAG-1-induced glioblastoma cell apoptosis.

Author information

1
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China; Postdoctoral research station of Neurosurgery, Wuhan General Hospital of Guangzhou Command, PLA, Wuhan, China.
2
Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an, China.
3
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
4
Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
5
Postdoctoral research station of Neurosurgery, Wuhan General Hospital of Guangzhou Command, PLA, Wuhan, China.

Abstract

Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) is a divergent member of the transforming growth factor-beta (TGF-β) superfamily. NAG-1 plays remarkable multifunctional roles in controlling diverse physiological and pathological processes including cancer. Like other TGF-β family members, NAG-1 can play dual roles during cancer development and progression by negatively or positively modulating cancer cell behaviors. In glioblastoma brain tumors, NAG-1 appears to act as a tumor suppressor gene; however, the precise underlying mechanisms have not been well elucidated. In the present study, we discovered that overexpression of NAG-1 induced apoptosis in U87 MG, U118 MG, U251 MG, and T98G cell lines via the intrinsic mitochondrial pathway, but not in A172 and LN-229 cell lines. NAG-1 could induce the phosphorylation of PI3K/Akt and Smad2/3 in all six tested glioblastoma cell lines, except Smad3 phosphorylation in A172 and LN-229 cell lines. In fact, Smad3 expression and its phosphorylation were almost undetectable in A172 and LN-229 cells. The PI3K inhibitors promoted NAG-1-induced glioblastoma cell apoptosis, while siRNAs to Smad2 and Smad3 decreased the apoptosis rate. NAG-1 also stimulated the direct interaction between Akt and Smad3 in glioblastoma cells. Elevating the level of Smad3 restored the sensitivity to NAG-1-induced apoptosis in A172 and LN-229 cells. In conclusion, our results suggest that PI3K/Akt and Smad-dependent signaling pathways display opposing effects in NAG-1-induced glioblastoma cell apoptosis.

PMID:
24759784
PMCID:
PMC3997521
DOI:
10.1371/journal.pone.0096283
[Indexed for MEDLINE]
Free PMC Article

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